Tuesday, April 30, 2013

Article Review (2000) - Curative hepatorenal transplantation in systemic amyloidosis caused by the Glu526Val fibrinogen alph-chain variant in an English family

This article review covers two firsts in fibrinogen amyloidosis. It is the first reported case of fibrinogen amyloidosis in an English patient, and it is the first detailed report of a combined liver and kidney transplant to treat fibrinogen amyoidosis.

TitleCurative hepatorenal transplantation in systemic amyloidosis caused by the Glu526Val fibrinogen alph-chain variant in an English family (1)

Authors: J.D. Gillmore, D.R. Booth, M. Rela, N.D. Heaton, V. Rahman,
A.J. Stangou , M.B. Pepys and P.N. Hawkins (National Amyloidosis Centre, King's College School of Medicine, and St. Mary's Hospital, all in the UK)

Journal: QJM: An International Journal of Medicine (2000)

A 53‐year‐old English woman who had been thought to have systemic monoclonal immunoglobulin light chain (AL) amyloidosis was investigated further because of her unusually long 17‐year history and a suggestion of renal disease in the family. She was found to have the Glu526Val fibrinogen alpha‐chain variant that causes autosomal dominant hereditary systemic amyloidosis. This has not previously been described in a British family. The mutant gene was associated with the same haplotype as in all other reported cases, suggesting a common founder. The patient had already received a renal transplant, but the graft failed within 6 years due to amyloid deposition. Progressive hepatic amyloidosis eventually caused liver failure, although the function of other organs was well preserved. She therefore received hepatic and renal transplants to replace the failed organs and the hepatic source of the amyloidogenic variant fibrinogen. Three years later she is completely well and has no amyloid deposits identifiable by serum amyloid P component scintigraphy. This is the first detailed report of hepatic transplantation for liver failure caused by amyloidosis of any type. The substantial follow‐up suggests that fibrinogen alpha‐chain amyloidosis is one of the inherited metabolic diseases that can be cured by liver transplantation. The mutation underlying Glu526Val fibrinogen alpha‐chain amyloidosis is incompletely penetrant and has a variable phenotype that can clinically mimic AL amyloidosis. Hereditary fibrinogen amyloidosis may be more prevalent than previously suspected and, since AL amyloid is sometimes a diagnosis of exclusion, genotyping for other amyloidogenic proteins is mandatory in all cases in which the amyloid fibrils cannot be positively identified as AL.
Here is a link to the article if you would like to follow along: http://qjmed.oxfordjournals.org/content/93/5/269.full

The Introduction of the article begins by stating that systemic amyloidosis can be either acquired or hereditary. It then states that hereditary amyloidosis usually has a major neuropathic component (we know those are typically transthyretin mutations), but there are some types of hereditary amyloidosis that cause renal impairment. It is important to note that the authors consider hereditary amyloidosis to be systemic, meaning it affects the body as a whole. AL amyloidosis is sometimes referred to as "systemic amyloidosis," but that can be misleading because hereditary amyloidosis is also systemic. (We will revisit this subject when we review some publications from 2010.)

The article then states that fibrinogen amyloidosis has previously been reported in eight kindreds, five of which have European ancestry and the Glu526Val mutation. Treatment up to this point has been either dialysis or a kidney transplant, but even with a kidney transplant, recurring amyloidosis can cause the transplanted kidney to fail or lead to amyloid involvement of other organs.

The Methods section of the article gives the patient's medical history and describes the various tests that were performed. One of these tests has not been previously described in the context of fibrinogen amyloidosis, and it does provide some interesting before and after graphical results. (More on that later.)

The patient was a woman of English ancestry who was experiencing renal failure in 1983 at the age of 36. A kidney biopsy showed amyloidosis which was thought to be AL amyloidosis. (This was before the first fibrinogen amyloidosis mutations were discovered in the early 1990s.) She went on hemodialysis and eventually received a kidney transplant in 1987. The transplanted kidney failed in 1993 due to recurrent amyloidosis and she went back on hemodialysis. In 1995 she started losing weight and experiencing abdominal pain due to an enlarged liver. In 1996 she was emaciated and had progressive liver failure. At this point doctors began investigating hereditary amyloidosis because her father had died of renal disease at the age of 66.

In addition to DNA analysis of the patient's blood, a biopsy of nasal mucosa (mucous membrane) obtained after a nosebleed was analyzed. Congo red staining did indicate amyloids, so it was then analyzed for the proteins known to cause familial amyloidosis, including fibrinogen.

The other test they did is called SAP scintigraphy. This test, which as far as I know is only done at the National Amyloidosis Centre in the UK, involves injecting a substance intravenously into the patient, then taking a picture 24 hours later to see where the substance is in the body. In overly simplistic and possibly incorrect terms, this substance (Serum Amyloid P) binds with amyloid deposits in the body. It is tagged with a radioactive tracer which enables a "picture" to be taken with a camera that detects the radiation. Here is an article describing it in great detail: http://www.amjmed.com/article/S0002-9343(05)00787-4/fulltext. If you just want to see what kind of images it gives, check these out: http://www.amjmed.com/article/S0002-9343(05)00787-4/journalimage?src=fig&loc=gr2&ishighres=false&allhighres=false&free=yes and read the notes at the bottom that tell what organs are affected in each set of images. We'll see some before and after images of this fibrinogen patient just a little later.

The Results section of the article gives the results of the various tests. They obviously discovered she had the fibrinogen Glu526Val mutation, although it is interesting that the nasal mucosa did not indicate fibrinogen as the source of the amyloids. The SAP scintigraphy showed that her liver and spleen were very heavily loaded with amyloid, such that they were unable to evaluate the amyloid load in other organs such as the kidneys.

This patient underwent a combined liver and kidney transplant in October of 1996. She was discharged from the hospital two weeks later with normal liver and kidney function. SAP scintigraphy 18 months after the transplant was normal, and at the time this article was written (36 months post-transplant) she had gained 20 kg (44 lbs.) in weight and had no symptoms of amyloidosis.

Below are the before and after SAP scintigraphy images from the article. The resolution isn't too good, but these are full-body scans with the head at the top of the picture. In the image on the left (pre-transplant), the large black area in the middle is where the radioactive tracer has collected, almost exclusively in the liver and spleen. In the image on the right (18 months post-transplant), the black areas correspond to large concentrations of blood in the body, which is normal, instead of being concentrated in one or more organs.


Here is the caption for this figure from the article:

Serial anterior whole body scintigraphic images in the patient after intravenous injection of (123)I-human SAP. Prior to hepatorenal transplantation (left) there is heavy amyloid deposition in the liver and spleen obscuring the kidneys. The image on the right was taken 18 months after hepatorenal transplantation and is normal, with tracer distributed throughout the blood-pool only. Serial scans over a further 18-month period have remained entirely normal.

The Discussion section of the article states that the two chief objectives in treating amyloidosis are to reduce the supply of the amyloid fibril precursor protein (fibrinogen in this case) and to use supportive therapy to replace failing organ function. For the patient described in this article they were able to offer a single procedure (liver-kidney transplant) that achieved both objectives. The failing organ was replaced (kidney), as was the source of the amyloid fibril precursor protein (liver). Quoting from the article: "The remarkably successful outcome supports the indication for liver transplantation in the management of this inherited metabolic disease . . ."

After discussing some of causes of the original misdiagnosis of AL amyloidosis in this case and what facts eventually caused them to question that diagnosis, they acknowledge that although they were unable to analyze tissue samples to isolate the amyloid fibrils, there are three pieces of evidence that indicate her amyloid deposits were of the fibrinogen alpha-chain type:

  1. DNA analysis indicated she had the Glu526Val fibrinogen alpha-chain mutation, which has previously been associated with systemic amyloidosis.
  2. "Secondly, three other mutations that cause hereditary amyloidosis have been identified in the same region of the fibrinogen alpha-chain gene, and amyloid fibrils composed of part of the corresponding variant fibrinogen alpha-chain have lately been isolated from a patient with one of these mutations." (I honestly don't follow the logic there, which is why I just copied that sentence from the article.)
  3. The regression of amyloid deposits in other organs after the liver transplant is indicative of the liver having been the source of the protein the caused the amyloid fibrils to form.

The article then discusses the use of solid organ transplantation in treating amyloidosis. In the case of fibrinogen amyloidosis, kidney transplants have been performed in several patients to date, and that is appropriate when other organs are not affected by amyloidosis. There was an unpublished report in 1998 of a liver-kidney transplant to treat a fibrinogen amyloidosis patient with heavy liver involvement, but no follow-up had been reported at the time this article was written. 

Liver transplantation has been widely used to treat familial amyloidosis caused by transthyretin mutations. The liver is the main source of transthyretin, and the livers of affected patients are not significantly affected by amyloids. So the livers from these patients have been used in domino transplants, which is when the liver removed from an amyloidosis patient is transplanted into a patient waiting on a liver transplant due to some other condition. A domino transplant would not have been possible in this case since this patient's liver was significantly affected by amyloid.

Referring again to fibrinogen amyloidosis, the article states that liver transplantation is potentially curative because there is no evidence that wild-type (naturally occurring) fibrinogen alpha-chain is amyloidogenic. Although they predicted this patient's amyloid deposits would gradually regress, they found the extent and speed with which that occurred to be quite remarkable.

The article closes with a paragraph discussing the importance of DNA analysis for patients with systemic amyloidosis in whom AL amyloid has not been positively confirmed, since a family history of hereditary amyloidosis is often not apparent due to variable penetrance (not everyone with the mutation develops clinically significant symptoms). They speculate "it is possible that the present mutation may be more common than has so far been recognized."


In this article from 2000 we have a case of someone with kidney failure at an earlier age than most fibrinogen amyloidosis patients (36), a kidney transplant at the age of 40 that failed six years later, followed by liver failure two years later, and then a liver-kidney transplant at the age of 49 which led to a remarkable recovery. That is a pretty strong indicator that a liver transplant may be a "cure" for fibrinogen amyloidosis. I would love to know how this patient is doing now (approximately 66 years old) and whether or not any other family members have been affected.

This article also introduces us to SAP scintigraphy, which is a way of imaging the amyloid deposits in the body. My understanding is that this technique does not have FDA approval for use in the US because the injected substance (Serum Amyloid P) is derived from the blood of healthy humans. We may get something similar in the US, however, because Dr. Solomon at the University of Tennessee is currently recruiting patients for an amyloidosis imaging study. Here is the link on the clinicaltrials.gov web site: http://clinicaltrials.gov/show/NCT01815086

The next article under review will also look into the issue of misdiagnosis and shed some more light on the commonality of the fibrinogen Glu526Val mutation.


(1) Gillmore JD, Booth DR, Rela M, et al. Curative hepatorenal transplantation in systemic amyloidosis caused by the Glu526Val fibrinogen alpha‐chain variant in an English family. QJ Med 2000; 93: 269-275.

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